Use of glucocorticoid receptor antagonist and somatostatin analogues to treat acth-secreting tumors

Abstract

Methods, compositions, and pharmaceutical formulations are provided for treatment of ACTH secreting tumors.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a U.S. National Phase Continuation Application of PCT / US2016 / 019646, filed Feb. 25, 2016, which claims priority to U.S. Provisional Application No. 62 / 127,153, filed Mar. 2, 2015, the contents of which are hereby incorporated in the entirety for all purposes.BACKGROUND OF THE INVENTION[0002]Adrenocorticotropic hormone (ACTH) is a polypeptide-based hormone that is normally produced and secreted by the anterior pituitary gland. ACTH stimulates secretion of cortisol and other glucocorticoids by specialized cells of the adrenal cortex. In healthy mammals, ACTH secretion is tightly regulated. ACTH secretion can be positively regulated by corticotropin releasing hormone (CRH), which is released by the hypothalamus. ACTH secretion can be negatively regulated by cortisol and other glucocorticoids.[0003]Aberrant ACTH-levels can lead to a wide variety of undesirable physiological conditions. For example, excess ACTH levels can ...

AI Technical Summary

Benefits of technology

The present invention provides a method of treating a subject with an adrenocorticotropic hormone (ACTH)-secreting tumor by simultaneously or sequentially administering a glucocorticoid receptor antagonist (GRA) and somatostatin or a somatostatin analog (SSA). The method reduces secretion of ACTH by the tumor. The invention also provides a glucocorticoid receptor antagonist (GRA) that can be used for the treatment. The invention can be applied to patients with Cushing's disease or ectopic ACTH syndrome. The treatment involves administering the GRA and SSA for at least two weeks. The invention also provides a fused azadeclin compound that can be used as a GRA. The technical effect of the invention is to provide a more effective treatment for ACTH-secreting tumors by reducing the secretion of ACTH and inhibiting the growth of the tumor.

Problems solved by technology

Aberrant ACTH-levels can lead to a wide variety of undesirable physiological conditions.

For example, excess ACTH levels can cause excess secretion of cortisol, resulting in hypercortisolemia or Cushing's Syndrome.

ACTH-secreting tumors arising from pituitary corticotroph cells (Cushing's disease) exhibit poor prognosis, and cause hypercortisolemia.

ACTH-secreting tumors can increase ACTH levels in a subject, resulting in excess cortisol secretion that can be associated with osteoporosis, infections, psychiatric disorders, muscle atrophy, fat accumulation, hypertension, hyperglycemia, or ultimately death.

Efficacies of other therapeutic modalities are limited by factors such as slow therapeutic response, development of pituitary insufficiency, and uncontrolled pituitary tumor growth in the face of adrenal gland resection or inhibition.

Effective pharmacotherapy directly targeting corticotroph tumor growth and / or ACTH secretion remains a major challenge.

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